phyrago

Important safety information

Myelosuppression and Bleeding Events: Severe thrombocytopenia, neutropenia, and anemia may occur. Use caution if used concomitantly with medications that inhibit platelet function or anticoagulants. Monitor complete blood counts regularly. Transfuse and interrupt PHYRAGO when indicated. ( 2.5 , 5.1 , 5.2 ) Fluid Retention: Fluid retention, sometimes severe, including pleural effusions. Manage with supportive care measures and/or dose modification. ( 2.5 , 5.3 ) Cardiovascular Toxicity: Monitor patients for signs or symptoms and treat appropriately. ( 5.4 ) Pulmonary Arterial Hypertension (PAH): PHYRAGO may increase the risk of developing PAH which may be reversible on discontinuation. Consider baseline risk and evaluate patients for signs and symptoms of PAH during treatment. Stop PHYRAGO if PAH is confirmed. ( 5.5 ) QT Prolongation: Use PHYRAGO with caution in patients who have or may develop prolongation of the QT interval. ( 5.6 ) Severe Dermatologic Reactions: Individual cases of severe mucocutaneous dermatologic reactions have been reported. ( 5.7 ) Tumor Lysis Syndrome: Tumor lysis syndrome has been reported. Maintain adequate hydration and correct uric acid levels prior to initiating therapy with PHYRAGO. ( 5.8 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of potential risk to fetus and to use effective contraception. ( 5.9 , 8.1 , 8.3 ) Effects on Growth and Development in Pediatric Patients: Epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia have been reported. Monitor bone growth and development in pediatric patients. ( 5.10 ) Hepatotoxicity: Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. ( 5.11 ) 5.1 Myelosuppression Treatment with dasatinib is associated with severe (NCI CTCAE Grade 3 or 4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML [see Adverse Reactions ( 6.1 )] . In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated. In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated. In pediatric patients with Ph+ ALL treated with PHYRAGO in combination with chemotherapy, perform CBCs prior to the start of each block of chemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, perform CBCs every 2 days until recovery. Myelosuppression is generally reversible; withhold, reduce, or discontinue PHYRAGO based on severity [see Dosage and Administration ( 2.5 )] . 5.2 Bleeding-Related Events PHYRAGO can cause serious and fatal bleeding. In all CML or Ph+ ALL clinical studies, Grade ≥3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving dasatinib. The incidence of Grade 3/4 hemorrhage occurred in 5.8% of adult patients and generally required treatment interruptions and transfusions. The incidence of Grade 5 hemorrhage occurred in 0.4% of adult patients. The most frequent site of hemorrhage was gastrointestinal [see Adverse Reactions ( 6.1 )] . Most bleeding events in clinical studies were associated with severe thrombocytopenia. In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage. 5.3 Fluid Retention PHYRAGO may cause fluid retention [see Adverse Reactions ( 6.1 )] . After 5 years of follow-up in the adult randomized newly diagnosed chronic phase CML study (n=258), Grade 3 or 4 fluid retention was reported in 5% of patients, including 3% of patients with Grade 3 or 4 pleural effusion. In adult patients with newly diagnosed or imatinib-resistant or -intolerant chronic phase CML, Grade 3 or 4 fluid retention occurred in 6% of patients treated with dasatinib at the recommended dose (n=548). In adult patients with advanced phase CML or Ph+ ALL treated with dasatinib, the recommended dose (n=304), Grade 3 or 4 fluid retention was reported in 8% of patients, including Grade 3 or 4 pleural effusion reported in 7% of patients. In pediatric patients with chronic phase CML, cases of Grade 1 or 2 fluid retention were reported in 10.3% of patients. Evaluate patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough, promptly with a chest x-ray or additional diagnostic imaging as appropriate. Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids. Severe pleural effusion may require thoracentesis and oxygen therapy. Consider dose reduction or treatment interruption [see Dosage and Administration ( 2.5 )] . 5.4 Cardiovascular Toxicity PHYRAGO can cause cardiac dysfunction [see Adverse Reactions ( 6.1 )] . After 5 years of follow-up in the randomized newly diagnosed chronic phase CML trial in adults (n=258), the following cardiac adverse reactions occurred: cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac-related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinib. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. 5.5 Pulmonary Arterial Hypertension PHYRAGO may increase the risk of developing pulmonary arterial hypertension (PAH) in adult and pediatric patients which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention [see Adverse Reactions ( 6.1 )] . PAH may be reversible on discontinuation of PHYRAGO. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating PHYRAGO and during treatment. If PAH is confirmed, PHYRAGO should be permanently discontinued. 5.6 QT Prolongation PHYRAGO may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy [see Adverse Reactions ( 6.1 )] . Correct hypokalemia or hypomagnesemia prior to and during PHYRAGO administration. 5.7 Severe Dermatologic Reactions Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome [see Adverse Reactions ( 6.2 )] and erythema multiforme, have been reported in patients treated with dasatinib. Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified. 5.8 Tumor Lysis Syndrome Tumor lysis syndrome has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease. Due to potential for tumor lysis syndrome, maintain adequate hydration, correct uric acid levels prior to initiating therapy with PHYRAGO and monitor electrolyte levels. Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequently [see Adverse Reactions ( 6.2 )] . 5.9 Embryo-Fetal Toxicity Based on limited human data, dasatinib can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects of dasatinib, including hydrops fetalis, fetal leukopenia,…